Title: | IκB-ζ Expression Requires Both TYK2/STAT3 Activity and IL-17–Regulated mRNA Stabilization |
Authors: | Muromoto, Ryuta Browse this author →KAKEN DB |
Tawa, Keisuke Browse this author |
Ohgakiuchi, Yui Browse this author |
Sato, Ami Browse this author |
Saino, Yuka Browse this author |
Hirashima, Koki Browse this author |
Minoguchi, Hiroya Browse this author |
Kitai, Yuichi Browse this author →KAKEN DB |
Kashiwakura, Jun-ichi Browse this author →KAKEN DB |
Shimoda, Kazuya Browse this author →KAKEN DB |
Oritani, Kenji Browse this author →KAKEN DB |
Matsuda, Tadashi Browse this author →KAKEN DB |
Issue Date: | 16-May-2019 |
Publisher: | The American Association of Immunologists |
Journal Title: | ImmunoHorizons |
Volume: | 3 |
Issue: | 5 |
Start Page: | 172 |
End Page: | 185 |
Publisher DOI: | 10.4049/immunohorizons.1900023 |
Abstract: | Cytokine IL-17A (IL-17) acts on various cell types, including epidermal keratinocytes, and induces antimicrobial peptide and chemokine production to elicit antibacterial and antifungal defense responses. Excess IL-17 leads to inflammatory skin diseases such as psoriasis. The IκB family protein IκB-ζ mediates IL-17–induced responses. However, the mechanism controlling IκB-ζ expression in IL-17–stimulated cells remains elusive. In this study, we showed that JAK kinase TYK2 positively regulates IL-17–induced IκB-ζ expression. TYK2-deficient mice showed reduced inflammation and concomitant reduction of IκB-ζ mRNA compared with wild-type mice in imiquimod-induced skin inflammation. The analysis of the IκB-ζ promoter activity using human cell lines (HaCaT and HeLa) revealed that catalytic activity of TYK2 and its substrate transcription factor STAT3, but not IL-17, is required for IκB-ζ promoter activity. In contrast, IL-17–induced signaling, which did not activate STAT3, posttranscriptionally stabilized IκB-ζ mRNA via its 3′-untranslated region. IL-17 signaling protein ACT1 was required to counteract constitutive IκB-ζ mRNA degradation by RNase Regnase-1. These results suggested that transcriptional activation by TYK2–STAT3 pathway and mRNA stabilization by IL-17–mediated signals act separately from each other but complementarily to achieve IκB-ζ induction. Therefore, JAK/TYK2 inhibition might be of significance in regulation of IL-17–induced inflammatory reactions. |
Rights: | http://creativecommons.org/licenses/by/4.0/ |
Type: | article |
URI: | http://hdl.handle.net/2115/82064 |
Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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